tbuckley/cabot-search huggingface dataset:
Leadership knowledge and beliefs regarding diversity, equity, and inclusion at SWOG Cancer Research Network.
Authors: Manuel Ricardo Espinoza Gutarra, Colmar Figueroa-Moseley, Lucy Gansauer, Gayathri Nagaraj, Jessica Dreger McDermott, Rick Bangs, Allison Caban-Holt, Patricia A. Robinson
Journal: Journal of Clinical Oncology (2023)

e13599 Background: Diversity, Equity, and Inclusion (DEI) is recognized as fundamental in the development of generalizable clinical trials. Both ASCO and the FDA have released statements regarding the importance of representativeness in clinical trials. A paucity of research exists regarding the knowledge and beliefs of the people who lead the development of trials within the NCTN. Methods: An electronic survey on knowledge and beliefs regarding DEI was administered to SWOG leadership from 12.14.2021 to 01.13.2022. Questions were divided into 4 categories including: general beliefs regarding DEI, SWOG’s current status regarding DEI efforts, perception of SWOG’s values and readiness in executing DEI. Twenty questions were asked and answers were recorded using a 5-point Likert scale. Results: A total of 53% (N=47/88) respondents completed the survey (Table 1). The majority of SWOG leadership strongly agree that diversity is an asset (68%) and that they have a role to champion DEI (72%). Less than a quarter of SWOG leadership strongly agree that there are sufficient opportunities for committee members to provide DEI input across the clinical trial life cycle (21%). When evaluating SWOGs current role in DEI efforts, 64% of respondents had a neutral or negative response for each of the 4 questions. When evaluating respondents’ perception of SWOG values regarding DEI, 64% of respondents had a positive or very positive response on average for each of the 6 questions. When evaluating SWOG’s readiness to promote DEI, 57% of respondents had a positive or very positive response for each question. Some of the barriers experienced include technological issues with construction and delivery of the survey to protected email addresses as well as lack of dedicated staff at SWOG to assist. Conclusions: This survey provides insight into SWOG leader’s beliefs and knowledge regarding DEI as well as their perception of SWOG’s current efforts and ability to promote DEI in clinical trials. While respondents tended to value DEI positively personally and through SWOG, their perception of SWOG’s role in promoting DEI was neutral or negative. Perception of SWOGs readiness to promote DEI was positive to a lesser degree. These findings emphasize the importance of capturing baseline beliefs to promote DEI efforts with clinical trial leadership. [Table: see text]
Tolerability and response of palliative radiotherapy in patients receiving tumor-infiltrating lymphocyte therapy.
Authors: Max Rogers, Grant McKenzie, Abbas Rattani, Mehran Yusuf, Jason Alan Chesney, Neal E. Dunlap
Journal: Journal of Clinical Oncology (2023)

e14527 Background: Tumor-infiltrating lymphocyte (TIL) therapy is an emerging therapeutic option for patients with metastatic tumors having progressed on multiple lines of systemic therapy. It is unknown how TIL therapy impacts the tolerability and effectiveness of palliative radiotherapy (RT). We herein present a case series of patients having received both TIL therapy and palliative RT along with the associated local responses and toxicity profiles. Methods: A single institution retrospective database review identified patients treated with TIL therapy following progression on ≥2 standard treatment(s) for metastatic disease. Patients were eligible for inclusion if they received palliative radiotherapy treatment within 1 year of TIL delivery as pre- or post-TIL therapy. Patient demographic data was collected and descriptive statistics reported. Radiographic imaging response was assigned in accordance with Response Evaluation Criteria in Solid Tumors (RECIST). Toxicities were graded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: Between 2017–2021, a total of 10 patients receiving TIL therapy treated across 12 courses of palliative RT were included for analysis. 8 of 10 patients (80%) had a primary diagnosis of malignant melanoma and 2 (20%) had non-small cell lung cancer. RT was administered to 7 patients pre- and 3 patients post-TIL therapy. Within the pre-TIL cohort, 2 patients received RT between TIL harvest and infusion. Patients received an average total dose of 26 Gy (range, 8-45 Gy). Median patient follow-up after RT was 6 months. Of the patients who received RT prior to TIL therapy, 6 of 9 sites demonstrated at-least stable disease at the site of RT versus 1 of 3 sites receiving post-TIL RT. Across the cohort, 2 patients experienced Grade 1 toxicities associated with RT treatment. No Grade 2+ events were reported. Conclusions: Palliative RT appears to be safe and tolerable when delivered both prior to and post-TIL therapy. RT may be an option for bridging therapy between TIL harvest and infusion. Local response rates to RT were greater in patients receiving RT prior to TIL infusion. Further investigations are warranted to determine the optimal dose, fractionation, and timing of RT when integrating it into future TIL therapy protocols. [Table: see text]
Therapeutic effect of a VSIG4-specific mAb EU103 in a preclinical model of patient-derived ascites of ovarian cancer.
Authors: Hye Jeong Kim, Kyung-Jung Kang, Jeamin Shin, Joong Won Lee, Byoung-Gie Kim, Sang-Yoon Park, Joseph H. Jeong, Byoung S. S Kwon
Journal: Journal of Clinical Oncology (2023)

e14516 Background: V-set and immunoglobulin domain-containing 4 (VSIG4) is one of the B7 family-related proteins that includes PD-L1, VISTA, and CTLA4 ligand. VSIG4 overexpression is correlated with poor prognosis in patients with ovarian cancer, lung cancer, gastric cancer, high-grade glioma, and multiple myeloma. VSIG4 is also known to function as a receptor for complements and the negative regulation of T cell proliferation. Although VSIG4 is highly expressed in tissue-resident macrophages and tumor-associated macrophages (TAM), its role in the tumor microenvironment (TME) is not fully elucidated. Methods: We previously developed a therapeutic antibody, EU103, in a humanized form of a VSIG4-specific antibody. Most importantly, we demonstrated that EU103 directly acts on the tumor-associated macrophages (TAM) and mechanistically induces repolarization of TAM to tumor killing M1 macrophages and blocks VSIG4-mediated T cell suppression, eventually leading to CD8 + T cell proliferation and tumor suppression in a PBMC-humanized human lung cancer mouse model. Results: Expanding our previous findings with the therapeutic potential of EU103 in a non-small cell lung carcinoma (NSCLC), here, we also proved its therapeutic effect in human ovarian cancer. Firstly, TAMs isolated from ovarian cancer patients express high levels of VSIG4 with immunosuppressive M2 macrophage phenotype. Secondly, EU103 treatment of the TAMs in in vitro studies induces M2-to-M1 conversion and activation of T cells in the ascites leading to ovarian tumor cell killing in a dose-dependent manner. Thirdly, in vivo therapeutic efficacy of EU103 in ovarian cancer, especially through M2-to-M1 conversion, is also verified in both CD34 + cell and peripheral blood mononuclear cell (PBMC) humanized mouse models. Finally, we validate the results above by treating ovarian cancer patient-derived ascites with EU103. Conclusions: Almost 300,000 women are diagnosed with ovarian cancer worldwide each year, and ovarian cancer ranks fifth in cancer deaths among women. In the United States alone, we expect approximately 20,000 new diagnoses and more than 12,000 deaths for this year. Given our findings in this study and clinical significance, we propose here the therapeutic potential of EU103, previously developed by our proprietary antibody discovery and engineering technology, in ovarian cancer.
Copy number variation (CNV) calling of MET, MYC, and ERBB2 using PiVAT bioinformatic platform.
Authors: Yao Yu, ShiPing Zou, Jing Wang, Bo Wang, Jing Sun, Dan Zhao, Xinyi Shi
Journal: Journal of Clinical Oncology (2023)

e15145 Background: CNV in tumor-associated genes such as MET, MYC and ERBB2 amplification can lead to cancer progression and poor survival in multiple cancers, and is associated with treatment regimen decision. Whole genome sequencing (WGS) and comprehensive genomic profiling (CGP) panels covering hundreds of genes are currently used to detect CNV in hospitals and CLIA-accredited laboratories. However, cost and complex workflow of WGS/CGP restrict their application in clinical molecular diagnostics. CGP panel covering dozens of genes based on targeted amplicon sequencing (TAS) method is preferred, but it is not ideal to detect CNV accurately due to unique methodology. Here we established a CNV calling toolkit in PiVAT bioinformatic platform to solve CNV calling problems in small-size TAS panel. Methods: 46 CNV positive (CNV+) and 14 CNV negative (CNV-) samples were sequenced using MGISEQ-2000 with a paired end, 2x100 read length protocol and adapter sequences were trimmed from 3’ ends of each read. PiVAT’s CNV calling method is based on double coverage normalization, including one per-sample normalization and one per-amplicon normalization. CNV- samples were used as normalization references. MET, MYC and ERBB2 copy number was investigated to determine sensitivity, specificity, precision, and accuracy of the overall test. Copy number deletion is defined as ratio &lt; 0.8 and amplification is defined as ratio &gt; 1.2. PiVAT CNV output calls were compared against excepted copy number to calculate and plot the concordance. CNVkit and Control-FREEC, 2 other CNV calling tools, were chosen as comparators to compare ERBB2, MET and MYC copy number levels with PiVAT’s CNV caller. Results: Sequencing results from all 46 CNV+ samples showed high coverage uniformity, with &gt; 90% of sites having base coverage depth &gt; 20% of mean coverage for all samples. Average mapping rate and on-target rate of sequencing run, analyzed by PiVAT, were 98.98±0.41% and 98.39±0.45%. Results from PiVAT showed a sensitivity of 97.83% and a specificity of 100% for MET, MYC, ERBB2 amplifications. PiVAT estimated copy number more accurately compared with CNVkit and Control-FREEC. PiVAT’s R 2 , measuring degree of difference from expected copy number, was greater than CNVkit and Control-FREEC for MET, MYC and ERBB2, with values at 0.78, 0.69 and 0.96, respectively. In contrast, CNVkit and Control-FREEC were on average 77.38% and 164.04% worse. For CNVkit and Control-FREEC, many of MET, MYC and ERBB2 CNV calls were seen at a much lower magnitude than expected. Conclusions: Our studies have shown that PiVAT is a reliable tool for calling CNVs. PiVAT’s sensitivity and accuracy were calculated to be &gt; 97%. And PiVAT outperformed other CNV calling tools, CNVkit and Control-FREEC. This demonstrates that PiVAT’s CNV caller can be used to provide CNV results from TAS panel, and guide relevant cancer diagnosis and clinical decision more accurately.
Symptom burden and end of life care in patients with acute myeloid leukemia undergoing intensive induction chemotherapy in a rural setting.
Authors: Sean O'Neil, Susan M Frankki, Lori J. Rosenstein
Journal: Journal of Clinical Oncology (2023)

e24117 Background: Patients with acute myeloid leukemia (AML) who receive intensive induction chemotherapy (IC) face a prolonged hospitalization and a life-threatening illness. As a result, patients experience a high physical, psychological, and emotional symptom burden which can significantly affect their quality of life (QOL). 1 There is also a high mortality rate associated with IC, with one study showing 12.3% chance of in-hospital death and 3.7% discharge to hospice. 2 Early integration of palliative care (IPC) has shown improvements in QOL, decrease in psychological stress and improved end-of-life care. 3 The aim of this study was to examine the historic use of IPC during IC and assess the symptom burden in a rural healthcare setting and to provide a rationale for early incorporation of palliative care into IC. Methods: We performed an IRB approved retrospective study of all patients with AML who were admitted to Gundersen Health System for IC from January 2013 to September 2021. Data collection included basic demographics, disease and treatment specific variables, and admission variables. Symptom burden was also assessed by reviewing daily progress notes. Statistical analysis included descriptive statistics, Wilcoxon signed-rank test, and Fisher’s exact test and was performed in SAS version 9.4 at a significance level of 0.05. Results: Our study included 33 patients with an average age of 62 years. Our sample was 100% white, 58% male, 82% married and 58% former smokers. Average length of stay was 29 days and 5 (15%) patients died during this time. Individuals experienced an average of 9.8 (range 4-17) of the 20 recorded symptoms, most commonly pain (97%), fevers (88%), edema (73%), anorexia (67%), rash (61%), and diarrhea (61%). Only 6 patients (18%) received a palliative care consultation during IC. For patients without a palliative care consultation during IC, advanced care planning (ACP) documents were found in only 37% during or before IC. However, when palliative care was consulted, ACP documentation increased to 83% demonstrating a trend towards significance (p = 0.07). There was a significant difference between the number of symptoms observed in those who received a palliative care consultation (median = 13 symptoms) and those who did not (median = 9 symptoms, p = 0.007). Conclusions: Despite our patients experiencing a high symptom burden and a significant chance of death, there was a low rate of early integration of palliative care. This retrospective study was unable to determine if IPC improved symptom burden, but we did find that IPC increased the rate of ACP documentation from 37% to 83%. The presence of ACP documentation has been shown to significantly reduce ICU utilization and improve the quality of care at the end of life. 4 Given these findings; we plan to move forward with routine integration of palliative care into the management of patients undergoing IC for AML.
XMT-1660: A phase 1b trial of a B7-H4 targeted antibody drug conjugate (ADC) in breast, endometrial, and ovarian cancers.
Authors: Erika P. Hamilton, Arvind Chaudhry, Alexander I. Spira, Sylvia Adams, Nour Abuhadra, Antonio Giordano, Ritesh Parajuli, Hyo S. Han, Amy M. Weise, Aubri Marchesani, Divya Gupta, Kate Josephs, Kevin Kalinsky
Journal: Journal of Clinical Oncology (2023)

TPS3154 Background: Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard of care (SOC) therapies. High B7-H4 expression has been observed in several cancers including breast, endometrial, and ovarian, with limited expression in normal tissue. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2- patient-derived xenograft mouse models, which included tumors from heavily pre-treated patients (Collins et al, AACR 2022). Increased anti-tumor activity tended to be more frequent in preclinical models with higher B7-H4 expression, providing rationale for a Ph1 clinical trial. Methods: The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary endpoints in DES are to assess safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary endpoint. In parallel with DES, optional backfill cohorts will enroll patients into tumor-type specific cohorts (TNBC, HR+/HER2- BC, EC, or OC) at a selected dose level from DES and can be initiated at multiple dose levels simultaneously. In the EXP portion, cohorts enrolling TNBC, ER+/HER2- BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary endpoint of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic analysis and assessment of antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumors samples are collected for retrospective tumor tissue evaluation. The trial is currently enrolling patients. NCT05377996. Clinical trial information: NCT05377996 .
Role of synthetic lethal mutations for the immune response: Exploratory studies of two non-small cell lung cancer cohorts and two pan-cancer cohorts.
Authors: Jun Wang, Miao Liu, Ding Zhang
Journal: Journal of Clinical Oncology (2023)

e21137 Background: Synthetic lethality (SL) is a phenomenon in which mutations in either of two genes do not affect cell survival, but abnormalities in both genes lead to cell death. However, it is little known whether synthetic lethality affects the response of immunotherapy. Methods: Synthetic lethal gene pairs come from the SynLethDB database, which provides a webserver to calculate the confidence scores for each SL pair by integrating individual scores derived from different evidence sources. The analysis included two immunotherapy cohorts of non-small cell lung cancer (Chan, 2015 and Hellmann, 2018) and two solid tumor cohorts (Morris, 2019 and Berger, 2020) in the published literature. Synthetic lethal gene pairs were defined as genes with a score &gt; 0.5. The patients with synthetic lethal gene pairs were divided into one subgroup (SL group), and the other patients were divided into another subgroup (non-SL group). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Overall, four public cohorts with 12271 patients were included in the analysis. In the cohort of Chan 2015, a total of 34 patients with non-small cell lung cancer (NSCLC) received immunotherapy. Among them, 21 patients were in the SL group and 13 were in the non-SL group, with the former having a significantly longer PFS (p = 0.0345). In the other cohort of immunotherapy (Hellmann, 2018), 90 (37.5%) patients with NSCLC were in SL group. PFS for patients with SL group was significantly longer than those in non-SL group (p = 0.0261). In cohorts with pan-cancer, patients in Morris 2019 cohort (n = 1661) received immunotherapy and patients in Berger 2020 cohort (n = 10336) received other kinds of treatment. A better prognosis was observed in patients with the immunotherapy in SL group than non-SL group (p &lt; 0.0001). In contrast, patients with other kinds of treatment had a significantly worse prognosis in SL group than non-SL group (p &lt; 0.0001). Conclusions: Our results suggested that synthetic lethal gene pairs containing scores greater than 0.5 may be associated with higher progression-free survival in patients with various types of tumors. The specific reasons for the impact still need to be further explored.
An ultra-sensitive amplicon-based NGS assay for MRD detection.
Authors: Liangjian Li, Meihong Chen, Shanshan Xiao, Lei Jia, Yalin Wu, Tao Wang
Journal: Journal of Clinical Oncology (2023)

e13634 Background: Detection of the minimal residual disease (MRD) has proven a promising noninvasive approach for monitoring the tumor remissions and relapses after surgical resection or other therapies. However, circulating tumor DNA (ctDNA) after surgery in the early-stage cancers can be at very low levels, which makes the MRD detection quite challengeable if the plasma sample only contains a few ctDNA copies. In the clinical practice, an ultra-sensitive and tumor-informed multiplexing variant detection system is required for postsurgical cancer surveillance. Methods: In this study we developed an ultra-sensitive amplicon-based NGS approach, namely UMIamp, to provide a personalized and tumor-informed strategy for MRD detection using plasma sample. Firstly, up to 16 clonal somatic variants can be obtained by whole exome sequencing (WES) of the tumor tissue samples. Then optimized primers were designed to uniformly cover the target DNA regions and those target regions were efficiently enriched by linear amplification. With randomly unique molecular identifiers (UMI) attached to DNA templates and ultra-deep NGS sequencing, the somatic target mutations with very low frequency can be identified using a customized bioinformatic pipeline. To validate the performance of the limit of detection (LOD), the reference standard samples were diluted to the allele frequencies of 0.02%, 0.01%, 0.005% and 0.002%, respectively. Each sample contained 14 single nucleotide variants (SNVs). The sensitivity and specificity were calculated based the mutations called. Results: Single site level sensitivity and specificity were 75% and 100% with the allele frequency of 0.02%, while they were 70.73% and 95.08% with the allele frequency of 0.01%. The results showed UMIamp was very sensitive and was able to detect 2 copies from 60ng cfDNA sample at 0.01% mutation level. Even at the 0.005% and 0.002% allele frequency levels there were less than two copies in 60ng cfDNA, UMIamp still achieved single site sensitivities of 24.18% and 23.07%, respectively. In the MRD clinical practice, sample level sensitivity was important to evaluate the detection capability based on more gene mutations. When combined the 14 variants as a unified indicator to detect the sample level MRD status, the positive rates at the VAFs of 0.02%, 0.01%, 0.005% and 0.002% were all 100%, which demonstrated the LOD of UMIamp approach can reach to as low as 0.002%. Such sensitivity will be adequate for post-surgical early-stage cancer surveillance. Conclusions: We developed an ultra-sensitive amplicon-based NGS approach which can effectively detect MRD status at the allele frequency of 0.002%. The developed approach can be applied in a personalized, tumor-informed MRD detection settings in post-surgical early-stage cancers.